Field of the Disclosure
The disclosure relates to lipid-based micro/nano-bubbles, and in particular, to a method of preparing lipid-based micro/nano-bubbles with a controlled diameter in a way of an optimal material utilization with an optimal bubble concentration.
Related Art
Micro-bubbles are commonly applied to function as an ultrasound contrast agent in form of fine bubbles with diameter of 1-5 μm encapsulated by a biodegradable material. Such micro-bubble-based ultrasound contrast agent can circulate well in the blood stream and provide a significant echo-enhancement of perfusion in ultrasound imaging. Micro-bubbles have a high degree of echogenicity because of their much lower density (compared with human tissues) and compressible inner. These characteristics allow bubbles to reflect the ultrasound waves and further oscillate with these waves. The echogenicity difference between the gas in the micro-bubbles and the soft tissue structures of the body is so significant that the ultrasound signal intensity may be enhanced by 20-40 dB. Thus, the micro-bubble-based ultrasound contrast agent can be used to image blood perfusion in organs, measure blood flow rate in the heart and other organs. Studies also show that micro-bubbles have the similar characteristics to the contrast mediums of other medical imaging systems for tumor diagnosis.
Another medical application for the micro-bubble-based ultrasound contrast agent is ultrasound molecular imaging. Through targeting ligand-conjugated micro-bubbles to specific biomarkers on target tissues, ultrasound imaging can be used to highlight those tissues, such as tumor, ischemia and inflammation areas, helping physicians achieving early detections of various diseases. The similar application to ultrasound molecular imaging is targeted therapy. Drug is encapsulated in the micro-bubbles to be injected into the blood vessel. Once the micro-bubbles are accumulated remarkably in target tissues, drug release is actively triggered by focused ultrasound. Ultrasound causes bubble destruction, which lowers the threshold for cavitation, resulting in micro streaming and increased permeability of cell membranes. In other words, micro-bubbles serve as a vehicle to carry the anti-tumor drug and locally release it when exposed to therapeutic ultrasound, which is referred to as ultrasound-triggered drug release. Several studies also showed the possibility of using micro/nano-bubbles to deliver genes into live cells.
However, as currently used micro-bubbles are relatively bigger in diameter and unstable in blood circulation. Those micro-bubbles are hard to reach a sufficient accumulation in target tissue in such a limited time. Lack of a preparation method with optimal material utilization efficiency (referred to lipid-to-bubble conversion ratio) also slows down the developments of functional micro-bubbles, such as ligand-conjugated, drug-encapsulated and nanoparticle-loaded micro-bubbles. Low material utilization efficiency results in a great loss of those costly functional compounds that makes the commercialization of functional micro-bubbles difficult. Therefore, it would be greatly desirable to have micro-bubbles which can be well controlled in diameter, stability, and material utilization efficiency (optimal material utilization efficiency).